Method of producing 3-aminoalkanoic acid esters

ABSTRACT

The invention relates to a method of producing 3-aminoalkanoic acid esters of the general formula (I), wherein R represents C 1-6  alkyl, and R 1  represents hydrogen, C 1-6  alkyl or phenyl, or the salts thereof, by catalytically hydrating the corresponding 3-amino-2-alkenoic acid esters in the presence of a strong acid.

[0001] The invention relates to a process for the preparation of3-aminoalkanoic acid esters from 3-amino-2-alkenoic acid esters.

[0002] Several processes for the hydrogenation of 3-amino-2-alkenoicacid esters are known.

[0003] RU-C-2 026 289 describes the hydrogenation of ethyl3-aminocrotonate in the presence of a nickel catalyst.

[0004] U.S. Pat. No. 4,585,887 describes the preparation of opticallyactive 3-aminoalkanoic acid esters, a β-ketoester being reacted with achiral amine and the enamine resulting therefrom being hydrogenated inthe presence of a Pt/C catalyst.

[0005] The hydrogenation rate and the selectivity are not satisfactoryin the abovementioned, known hydrogenation processes.

[0006] The object of the present invention was to make available aprocess for the preparation of 3-aminoalkanoic acid esters from3-amino-2-alkenoic acid esters, the hydrogenation proceeding rapidly andwith high selectivity.

[0007] According to the invention, this object is achieved by theprocess according to claim 1.

[0008] It has now been found that catalytic hydrogenation proceeds veryrapidly in the presence of a strong acid and 3-aminoalkanoic acid estersare obtained in high yield.

[0009] The process according to the invention relates to the preparationof 3-aminoalkanoic acid esters of the general formula

[0010] in which R is C₁₋₆-alkyl and R¹ is hydrogen, C₁₋₆-alkyl orphenyl, or their salts, by catalytic hydrogenation of the corresponding3-amino-2-alkenoic acid esters of the general formula

[0011] in which R and R¹ have the abovementioned meanings.

[0012] The process is characterized in that the catalytic hydrogenationis carried out in the presence of a strong acid and the salt of the3-aminoalkanoic acid ester (I) and the strong acid formed is optionallyconverted into the free 3-aminoalkanoic acid ester (I) or into anothersalt in a manner known per se.

[0013] C₁₋₆-alkyl is understood here and below as meaning all linear orbranched alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl orisohexyl.

[0014] The radical R is preferably methyl.

[0015] Strong acids here and below are in particular understood asmeaning hydrohalic acids, such as, for example, hydrochloric orhydrobromic acid, sulfuric acid, sulfonic acids, such as, for example,methanesulfonic, benzenesulfonic or p-toluenesulfonic acid, andperfluoro-alkanoic acids.

[0016] The strong acid is expediently employed in an equimolar amount orin a small excess, based on the ester.

[0017] A preferred hydrohalic acid is hydrochloric acid.

[0018] Suitable sulfonic acids are, for example, methanesulfonic acid orp-toluenesulfonic acid.

[0019] Trifluoroacetic acid is a preferred perfluoro-alkanoic acid.

[0020] Suitable catalysts are, in particular, platinum, palladium orrhodium catalysts, in particular supported catalysts. A platinumsupported catalyst is particularly preferred.

[0021] Suitable support materials are all customary support materialssuch as, for example, activated carbon, alumina, silica, siliconaluminum oxide, silicon carbide, titania, magnesia or zeolites.Activated carbon is preferred.

[0022] The supported catalysts contain expediently approximately 1-30%by weight, preferably approximately 5-10% by weight, of noble metal.

[0023] Catalysts of this type are commercially obtainable, e.g. fromDegussa or Heraeus.

[0024] The hydrogenation is expediently carried out in an anhydroussolvent.

[0025] Suitable solvents are in particular those from the group of thelower alcohols (e.g. methanol, ethanol), esters (e.g. methyl acetate),ethers (e.g. tetrahydrofuran, dioxane, diethyl ether) or haloalkanes(e.g. dichloro-methane, 1,2-dichloroethane). Anhydrous methanol isespecially preferred.

[0026] The hydrogenation is expediently carried out at temperatures of0-150° C. and pressures of 1-100 bar, preferably at room temperature(20-30° C.) and pressures of 5-10 bar.

[0027] The 3-amino-2-alkenoic acid esters (II) can be obtained byreaction of ammonia with 3-oxoalkanoic acid esters, as described in theabovementioned Russian patent publication.

[0028] A further possibility for the preparation of 3-amino-2-alkenoicacid esters (II) is the ring-opening of β-lactams described in DE-A-2425 705 and subsequent esterification by reaction with alcohol/HCl.

[0029] The methanesulfonates of the 3-ammonioalkanoic acid esters of thegeneral formula

[0030] in which R and R¹ have the abovementioned meanings, are novel andlikewise a subject of the invention.

[0031] The conversion of the salt of the 3-aminoalkanoic acid ester (I)and the strong acid into the free 3-aminoalkanoic acid ester (I) can becarried out in a manner known per se, for example by addition of sodiumhydroxide solution.

[0032] The following examples illustrate the implementation of theprocess according to the invention, without a restriction being seentherein.

EXAMPLE 1

[0033] Preparation of Methyl (RS)-3-Aminobutyrate Hydrochloride (In thePresence of Hydrochloric Acid)

[0034] 5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of a 9.3%strength solution of 17 g (43 mmol) of HCl gas in anhydrous methanol and0.22 g of Pt/C catalyst (Heraeus K0129) were introduced into a 160 mlParr autoclave. The hydrogenation was carried out for 3 hours at 21-25°C. under 5-10 bar of hydrogen. The catalyst was then filtered off andthe solvent was completely removed by distillation on a rotaryevaporator. 6.34 g of pure methyl (RS)-3-amino-butyrate hydrochloridewere obtained as an oil.

EXAMPLE 2

[0035] Preparation of Methyl (RS)-3-Aminobutyrate Sulfate or HydrogenSulfate (In the Presence of Sulfuric Acid)

[0036] 5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of anhydrousmethanol, 1.5 equivalent of sulfuric acid and 0.22 g of Pt/C catalyst(Heraeus K0129) were introduced into a 160 ml Parr autoclave. Thehydrogenation was carried out for 2 hours at approximately 25° C. under3-10 bar of hydrogen. The catalyst was then filtered off and the solventwas completely removed by distillation on a rotary evaporator. 6.13 g ofpure methyl (RS)-3-aminobutyrate sulfate were obtained as an oil. Thehydrogensulfate can be prepared correspondingly.

EXAMPLE 3

[0037] Preparation of Methyl (RS)-3-Aminobutyrate Methanesulfonate (Inthe Presence of Methanesulfonic Acid)

[0038] 5.0 g (43.4 mmol) of methyl 3-aminocrotonate, 70 ml of anhydrousmethanol, 1.0 equivalent of methanesulfonic acid and 0.22 g of Pt/Ccatalyst (Heraeus K0129) were introduced into a 160 ml Parr autoclave.The hydrogenation was carried out for 2 hours at approximately 20° C.under 5-10 bar of hydrogen. The catalyst was then filtered off and thesolvent was completely removed by distillation on a rotary evaporator.6.2 g of pure methyl (RS)-3-aminobutyrate methanesulfonate were obtainedas an oil.

[0039] A sample was crystallized from tetrahydrofuran forcharacterization.

[0040] m.p.: 83-85° C.

1. Process for the preparation of 3-aminoalkanoic acid esters of thegeneral formula

in which R is C₁₋₆-alkyl and R¹ is hydrogen, C₁₋₆-alkyl or phenyl, ortheir salts, by catalytic hydrogenation of the corresponding3-amino-2-alkenoic acid esters of the general formula

in which R and R¹ have the abovementioned meanings, characterized inthat the hydrogenation is carried out in the presence of a strong acidand the salt of the 3-aminoalkanoic acid ester (I) and the strong acidformed is optionally converted into the free 3-aminoalkanoic acid ester(I) or into another salt in a manner known per se.
 2. Process accordingto claim 1, characterized in that the strong acid employed is an acidfrom the group consisting of the hydrohalic acids, sulfuric acid,sulfonic acids and perfluoroalkanoic acids.
 3. Process according toclaim 2, characterized in that the strong acid employed is hydrochloricacid, methanesulfonic acid, p-toluenesulfonic acid or trifluoro-aceticacid.
 4. Process according to one of claims 1 to 3, characterized inthat the catalyst employed is a platinum, palladium or rhodium supportedcatalyst.
 5. Process according to claim 4, characterized in that thesupported catalyst employed is platinum on activated carbon.
 6. Processaccording to one of claims 1 to 5, characterized in that R is methyl. 7.Process according to one of claims 1 to 6, characterized in that thehydrogenation is carried out in an anhydrous solvent.
 8. Processaccording to claim 7, characterized in that the hydrogenation is carriedout in a solvent from the group consisting of the lower alcohols,esters, ethers or haloalkanes.
 9. 3-Ammonioalkanoic acid estermethanesulfonates of the general formula

in which R and R¹ have the meanings mentioned in claim
 1. 10. Methyl(RS)-3-ammoniobutyrate methanesulfonate.